MDSC targeting with Gemtuzumab ozogamicin restores T cell immunity and immunotherapy against cancers

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MDSC targeting with Gemtuzumab ozogamicin restores T cell immunity and immunotherapy against cancers. / Fultang, Livingstone; Panetti, Silvia; Ng, Margaret; Collins, Paul; Graef, Suzanne; Rizkalla, Nagy; Booth, Sarah; Richard, Lenton; Noyvert, Boris; Shannon-Lowe, Claire; Middleton, Gary; Mussai, Francis; De Santo, Carmela.

In: EBioMedicine, Vol. 47, 01.09.2019, p. 235-246.

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@article{8948c4756a344b328de152f288d09ea8,
title = "MDSC targeting with Gemtuzumab ozogamicin restores T cell immunity and immunotherapy against cancers",
abstract = "BackgroundTargeting of MDSCs is a major clinical challenge in the era of immunotherapy. Antibodies which deplete MDSCs in murine models can reactivate T cell responses. In humans such approaches have not developed due to difficulties in identifying targets amenable to clinical translation.MethodsRNA-sequencing of M-MDSCs and G-MDSCs from cancer patients was undertaken. Flow cytometry and immunohistochemistry of blood and tumours determined MDSC CD33 expression. MDSCs were treated with Gemtuzumab ozogamicin and internalisation kinetics, and cell death mechanisms determined by flow cytometry, confocal microscopy and electron microscopy. Effects on T cell proliferation and CAR-T cell anti-tumour cytotoxicity were identified in the presence of Gemtuzumab ozogamicin.FindingsRNA-sequencing of human M-MDSCs and G-MDSCs identified transcriptomic differences, but that CD33 is a common surface marker. Flow cytometry indicated CD33 expression is higher on M-MDSCs, and CD33+ MDSCs are found in the blood and tumours regardless of cancer subtype. Treatment of human MDSCs leads to Gemtuzumab ozogamicin internalisation, increased p-ATM, and cell death; restoring T cell proliferation. Anti-GD2-/mesothelin-/EGFRvIII-CAR-T cell activity is enhanced in combination with the anti-MDSC effects of Gemtuzumab ozogamicin.InterpretationThe study identifies that M-MDSCs and G-MDSCs are transcriptomically different but CD33 is a therapeutic target on peripheral and infiltrating MDSCs across cancer subtypes. The immunotoxin Gemtuzumab ozogamicin can deplete MDSCs providing a translational approach to reactivate T cell and CAR-T cell responses against multiple cancers. In the rare conditions of HLH/MAS gemtuzumab ozogamicin provides a novel anti-myeloid strategy.FundThis work was supported by Cancer Research UK, CCLG, Treating Children with Cancer, and the alumni and donors to the University of Birmingham.",
keywords = "CAR-T, CD33, Cancer, Gemtuzumab, MDSC",
author = "Livingstone Fultang and Silvia Panetti and Margaret Ng and Paul Collins and Suzanne Graef and Nagy Rizkalla and Sarah Booth and Lenton Richard and Boris Noyvert and Claire Shannon-Lowe and Gary Middleton and Francis Mussai and {De Santo}, Carmela",
year = "2019",
month = sep
day = "1",
doi = "10.1016/j.ebiom.2019.08.025",
language = "English",
volume = "47",
pages = "235--246",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - MDSC targeting with Gemtuzumab ozogamicin restores T cell immunity and immunotherapy against cancers

AU - Fultang, Livingstone

AU - Panetti, Silvia

AU - Ng, Margaret

AU - Collins, Paul

AU - Graef, Suzanne

AU - Rizkalla, Nagy

AU - Booth, Sarah

AU - Richard, Lenton

AU - Noyvert, Boris

AU - Shannon-Lowe, Claire

AU - Middleton, Gary

AU - Mussai, Francis

AU - De Santo, Carmela

PY - 2019/9/1

Y1 - 2019/9/1

N2 - BackgroundTargeting of MDSCs is a major clinical challenge in the era of immunotherapy. Antibodies which deplete MDSCs in murine models can reactivate T cell responses. In humans such approaches have not developed due to difficulties in identifying targets amenable to clinical translation.MethodsRNA-sequencing of M-MDSCs and G-MDSCs from cancer patients was undertaken. Flow cytometry and immunohistochemistry of blood and tumours determined MDSC CD33 expression. MDSCs were treated with Gemtuzumab ozogamicin and internalisation kinetics, and cell death mechanisms determined by flow cytometry, confocal microscopy and electron microscopy. Effects on T cell proliferation and CAR-T cell anti-tumour cytotoxicity were identified in the presence of Gemtuzumab ozogamicin.FindingsRNA-sequencing of human M-MDSCs and G-MDSCs identified transcriptomic differences, but that CD33 is a common surface marker. Flow cytometry indicated CD33 expression is higher on M-MDSCs, and CD33+ MDSCs are found in the blood and tumours regardless of cancer subtype. Treatment of human MDSCs leads to Gemtuzumab ozogamicin internalisation, increased p-ATM, and cell death; restoring T cell proliferation. Anti-GD2-/mesothelin-/EGFRvIII-CAR-T cell activity is enhanced in combination with the anti-MDSC effects of Gemtuzumab ozogamicin.InterpretationThe study identifies that M-MDSCs and G-MDSCs are transcriptomically different but CD33 is a therapeutic target on peripheral and infiltrating MDSCs across cancer subtypes. The immunotoxin Gemtuzumab ozogamicin can deplete MDSCs providing a translational approach to reactivate T cell and CAR-T cell responses against multiple cancers. In the rare conditions of HLH/MAS gemtuzumab ozogamicin provides a novel anti-myeloid strategy.FundThis work was supported by Cancer Research UK, CCLG, Treating Children with Cancer, and the alumni and donors to the University of Birmingham.

AB - BackgroundTargeting of MDSCs is a major clinical challenge in the era of immunotherapy. Antibodies which deplete MDSCs in murine models can reactivate T cell responses. In humans such approaches have not developed due to difficulties in identifying targets amenable to clinical translation.MethodsRNA-sequencing of M-MDSCs and G-MDSCs from cancer patients was undertaken. Flow cytometry and immunohistochemistry of blood and tumours determined MDSC CD33 expression. MDSCs were treated with Gemtuzumab ozogamicin and internalisation kinetics, and cell death mechanisms determined by flow cytometry, confocal microscopy and electron microscopy. Effects on T cell proliferation and CAR-T cell anti-tumour cytotoxicity were identified in the presence of Gemtuzumab ozogamicin.FindingsRNA-sequencing of human M-MDSCs and G-MDSCs identified transcriptomic differences, but that CD33 is a common surface marker. Flow cytometry indicated CD33 expression is higher on M-MDSCs, and CD33+ MDSCs are found in the blood and tumours regardless of cancer subtype. Treatment of human MDSCs leads to Gemtuzumab ozogamicin internalisation, increased p-ATM, and cell death; restoring T cell proliferation. Anti-GD2-/mesothelin-/EGFRvIII-CAR-T cell activity is enhanced in combination with the anti-MDSC effects of Gemtuzumab ozogamicin.InterpretationThe study identifies that M-MDSCs and G-MDSCs are transcriptomically different but CD33 is a therapeutic target on peripheral and infiltrating MDSCs across cancer subtypes. The immunotoxin Gemtuzumab ozogamicin can deplete MDSCs providing a translational approach to reactivate T cell and CAR-T cell responses against multiple cancers. In the rare conditions of HLH/MAS gemtuzumab ozogamicin provides a novel anti-myeloid strategy.FundThis work was supported by Cancer Research UK, CCLG, Treating Children with Cancer, and the alumni and donors to the University of Birmingham.

KW - CAR-T

KW - CD33

KW - Cancer

KW - Gemtuzumab

KW - MDSC

UR - http://www.scopus.com/inward/record.url?scp=85072261497&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2019.08.025

DO - 10.1016/j.ebiom.2019.08.025

M3 - Article

VL - 47

SP - 235

EP - 246

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

ER -